We investigated the effects of either intravenous (IV) or intrabronchial (IB) treatment with transforming growth factor beta1 (TGF-beta1) during bacterial pneumonia in rats. Immediately following IB Escherichia coli inoculation (T0), animals (n=270) were randomized to receive a single treatment with human recombinant TGF-beta1 either via IV or IB, or via both IV and IB routes, or to receive placebo (human serum albumin, HSA) only. Blood and lung analysis was done at 6 and 168 h after E. coli inoculation. Other animals (n=40) were administered IV TGF-beta1 or HSA at T0 and 6, 12 and 24 h after E. coli inoculation to investigate the effects of multiple treatments also on survival rates alone. All animals received ceftriaxone daily. Route of administration did not influence TGF-beta1 (p=ns for the effect of TGF-beta1 comparing IV vs IB routes) and we averaged over this variable in analysis. The relative risk of death (mean +/- sem) was not altered by either single treatments administered at T0 (-0.18 +/- 0.25, p=0.47) or multiple treatments (0.40 +/- 0.50, p=0.66) of TGF-beta1. Single treatment with TGF-beta1 first decreased and then increased vascular leukocytes at 6 and 168 h, respectively, but increased alveolar leukocytes at both time points (p=0.02 comparing the differing effects of TGF-beta1 on vascular and alveolar leukocytes at 6 and 168 h). Although TGF-beta1 decreased blood and lung bacteria counts at 6 and 168 h, it also increased serum tumor necrosis factor levels and lung injury scores at these time points (p<0.05 for the effects of TGF-beta1 on each parameter at 6 and 168 h together). Thus, while increases in lung leukocyte recruitment with TGF-beta1 were associated with improved microbial clearance in this rat model of pneumonia, worsened lung injury may have negated these beneficial host defense effects, and overall survival was not significantly improved. Despite these harmful effects, additional studies may be warranted to better define the influence of exogenous TGF-beta1 on host defense during acute bacterial infections.